Dr. Yan Xiao

Development of Biomarker-based Systems for Cancer Detection and Therapy.

Biomarkers play an increasingly more important role in disease detection and treatment. By applying front-end technologies and novel materials such as single-walled carbon nanotubes (SWCNTs) and quantum dots (Qdots), we are developing biomarker-based systems that are potentially useful for the detection and treatment of cancers. 

Discovery of new cancer biomarkers using high-throughput technologies.

Our lab is actively involved in various stages of cancer biomarker development along three lines of research. The first is to discovery of new cancer biomarkers. Mitochondrial DNA (mtDNA) is considered more susceptible to environmental damages than genomic DNA. As a result, mtDNA lesions may accumulate in the cell and ultimately lead to malignant transformation. In the last years, mtDNA lesions have been discovered to be characteristic of many cancers. We have a project to identify oxidatively induced mtDNA lesions correlated with mitochondrial function changes in cancer cell lines as potential biomarkers for early cancer detection. We use LC/MS/MS and GC/MS to measure the levels of DNA base lesions in the mitochondrial genome.

Validation of newly identified cancer biomarkers in clinical settings.

As the second line of research, we are validating newly identified cancer biomarkers with clinical tissue samples. Many of these biomarkers are proteins which demand accurate quantitation in order to provide meaningful information for clinical decision making. Immunohistochemistry (IHC) has been used traditionally for analyzing protein analytes at the single cell level. However, conventional IHC methods suffered from their nonquantitative nature due to photobleaching of organic fluorophores used. To overcome the hurdle, we have developed, a quantitative immunohistochemical (IHC) assay method using quantum dot (Qdot), a semiconductor nanocrystal, as fluorophore. To improve assay specificity and sensitivity, we have also developed novel IgY antibodies for biomarkers HER2 and telomerase and demonstrated their superiority over mammalian IgGs in the Qdot-based IHC system. We are currently using this system to validate multiple biomarkers of the PI3K/AKT/mTOR pathway including PTEN, mTOR, 4E-BP1 and HER2, which are potential markers of prostate and breast cancer progression.

Translation of validated biomarkers into potentially useful clinical applications.

Our third line of research focuses on translation established biomarkers into potentially useful clinical applications. HER2 (human epidermal growth factor receptor 2) is an example of such a biomarker whose status plays a pivotal role in therapeutic decision making for patients with breast cancer and in determining their clinical outcomes. Along this line of research, we have developed HER2-based systems employing front-end technologies and novel materials. One such technology is single-walled carbon nanotubes (SWCNTs). SWCNTs have strong Raman signals and NIR absorption, which can be exploited to facilitate cancer detection and therapy. We have constructed a HER2 IgY-SWCNT complex by covalently functionalizing SWCNTs with anti-HER2 IgY antibody and demonstrated its dual functionality for both detection and selective photothermal ablation of breast cancer cells in an in vitro model. As an advantage of this system, it does not require internalization by the cancer cells in order to achieve the selective destruction. We are currently extending the application of this system to other cancers.  

 

Scientific Awards:

Best Paper Award at 25th Army Science Conference, November 27-30, 2006, Orlando, Florida

Patents:

Xiao Y, IgY antibodies to human telomerase reverse transcriptase. US Patent Pub. App. No. US 20080131442.

Xiao Y, He H, Gao X, Taratula O, Urbas A, Wagner PD and Srivastava S, Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells, 2010, US Patent Application No. 61/310329.

Xiao Y, He H, Gao X, Cheung W, Taratula O, Wagner PD and Srivastava S, A new method for the construction of anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes with improved properties for detection and selective destruction of breast cancer cells, 2010, US Patent Application No. 61/310324.

Publications:

Xiao Y, Forry SP, Gao X, Holbrook RD, Telford WG, and Tona A, Dynamics and mechanisms of quantum dot nanoparticle cellular uptake, BMC Journal of Nanobiotechnology, 2010, in press.

Xiao Y and Gao X, Use of IgY Antibodies and Semiconductor Nanocrystal Detection in Cancer Biomarker Quantitation, Biomarkers Med., 2010, in press.

Xiao Y and Gao X, Quantum Dots for Cancer Imaging, Nanomaterials for the Life Sciences Vol. 6, Semiconductor Nanomaterials for Life Sciences, pp. 3-61, Wiley-VCH Verlag GmbH & Co., 2010.

Pawel Jaruga, Xiao Y, Vladimir Vartanian, R. Stephen Lloyd and Miral Dizdaroglu, Evidence for the involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision Repair of (5'R)- and (5'S)-8,5'-Cyclo-2'-deoxyadenosines, Biochemistry, 2010, 49:1053-1-55.

Gao X, Ray R, Xiao Y, Ishida K and Ray P, Macrolide antibiotics improve phagocytic capacity and reduce inflammation in sulfur mustard-exposed monocytes. Pulmonary Pharmacology and Therapeutics, 2010, 23(2): 97–106.

Xiao Y, Gao X, Taratula O, Treado S, Urbas A, Holbrook D, Cavicchi R, Avedisian T, Mitra S, Savla R, Wagner P, Srivastava S. and He H, Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells. BMC Cancer, 2009, 9:351.

Jaruga P, Xiao Y, Nelson BC and Dizdaroglu M, Measurement of (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines in DNA in vivo by liquid chromatography/ isotope-dilution tandem mass spectrometry Corresponding, Biochemical and Biophysical Research Communications, 2009, 386: 656–660.

Xiao Y, Gao X, Maragh S, Teleford WG and Tona A, Cell lines as candidate reference material for quality control of HER2 amplification and expression assays in breast cancer. Clin Chem, 2009, 55:1307-1315.

Xiao Y, Barker PE: Cellular bioimaging in fluorescent cancer biomarker evaluation: validation, technologies and standards development. In Standardization and Quality Assurance in Fluorescence Measurements II: Bioanalytical and Biomedical Applications. Edited by Resch-Genger U. Berlin Heidelberg: Springer; 2008:511-530. [Wolfbeis OS (Series Editor): Springer Series on Fluorescence, Vol 6.]

Xiao Y et al: Validating cancer biomarkers. In Validating Cancer Biomarkers Technical Guide. Edited by Swanson J. Genome Technology Online; ( http://www.genomeweb.com/pdfs/Guide1108-CancerBiomarkers.pdf.) November 2008:6-14. [Swanson J (Series Editor): Genome Technology Technical Guide, November 2008].

Xiao Y, Gao X, Gannot G, Emmert-Buck MR, Srivastava S, Wagner PD, Amos MD, Barker PE: Quantitation of HER2 and telomerase biomarkers in solid tumors with IgY antibodies and nanocrystal detection. Int J Cancer 2008, 122: 2178-2186.

Gao X, Ray R, Xiao Y, Ray P: Suppression of inducible nitric oxide synthase expression and nitric oxide production by macrolide antibiotics in sulfur mustard-exposed airway epithelial cells. Basic Clin Pharmacol Toxicol 2008, 103:255-261.

Gao X, Ray R, Xiao Y, Barker PE, Ray P: Inhibition of sulfur mustard-induced cytotoxicity and inflammation by the macrolide antibiotic roxithromycin in human respiratory epithelial cells. BMC Cell Biol 2007, 8:17.

Müller F, Houben A, Barker PE, Xiao Y, Käs JA, Melzer M. Quantum dots – a versatile tool in plant science? J Nanobiotechnology 2006, 4:5.

Xiao Y, Telford WG, Ball JC, Locascio LE, Barker PE: Semiconductor nanocrystal conjugates, FISH and pH. Nat Methods 2005, 2:723.

Xiao Y, Barker PE: Semiconductor Nanocrystal Probes for Human Chromosomes and DNA. Minerva Biotecnol 2004, 16:281-288.

Xiao Y, Barker PE: Semiconductor nanocrystal probes for human metaphase chromosomes. Nucleic Acids Res 2004, 32:e28.

Xiao Y, Constance L. Monitto, Khalid M. Minhas and David Sidranssky: Lactoferrin Downregulates G1 Cyclin-Dependent Kinases during Growth Arrest of Head and Neck Cancer Cells. Clinical Cancer Research 2004, 10, 8683-8686.

Tokumaru Y, Yamashita K, Osada M, Nomoto S, Xiao Y, Hoque MO, Westra WH, Califano JA, and Sidransky D, Inverse Correlation between Cyclin A1 Hypermethylation and p53 Mutation in Head and Neck Cancer Identified by Reversal of Epigenetic Silencing. Cancer Research 2004, 64, 5982–5987,

Yamashita K, Upadhyay S, Osada M, Hoque MO, Xiao Y, Mori M, Sato F, Meltzer SJ, Sidransky D. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2002, 2, 485-95.

Paola Parrella, Yan Xiao, Makiko Fliss, Montserrat Sanchez-Cespedes, Paola Mazzarelli and David Sidransky, Detection of Mitochondrial DNA Mutation in Primary Breast Cancer and Fine-Needle Aspirates. Cancer Research 2001, 61, 7623-7626

Montserrat Sanchez-Cespedes, Paola Parrella Shuji Nomoto, Yan Xiao, Daniel Cohen, Carmen Jeronimo, David Sidransky, Identification of a Mononucleotide Repeat as a Major Target for Mitochondrial DNA Alterations in Human Tumors. Cancer Research 2001, 61, 7015-7019.

Yan Xiao, Mark Metzl and David M. Mueller, Semi-dominant negative effect of null mutations in the genes encoding the gamma and delta subunits of the yeast mitochondrial ATPase. J. Biol. Chem. 2000, 275, 6963-6968

Jie Lai-Zhang, Yan Xiao and David M. Mueller, Epistatic interactions of deletion mutants in the genes encoding the F1-ATPase in yeast S. cerevisiae. The EMBO Journal 1999, 18, 58-64.

Lu Bin, Yan Xiao, Jianxing Xu and Lianquan Gu, The inhibitory effect of azidosalicylic amides on the succinate-ubiquinone reductase and ubiquinol-cytochrome c activities of purified succinate-cytochrome c reductase. Chinese Journal of Biochemistry and Molecular Biology 1999, 15, 131-134

Yan Xiao, Shusen Liu, Longmei Zen and Lianquan Gu, A study on the nitochondrial respiratory chain of aquatic animals. Acta Zoologica Sinica 1998, 44, 219-225

Yan Xiao, Lian-quan Gu and Jian-xing Xu, Synthesis of azidosalicylamides ( a new molecular probe of mitochondrial oxido-reductase inhibitor type). Chinese Journal of Organic Chemistry 1997, 17, 354-358

Jian-xing Xu, Yan Xiao, Yi-huang Wang, Xun Li and Lian-quan Gu, Comparison between the properties of 3-nitrosalicyl-N-alkylamide and antimycin A acting on QH2:cytochrome c reductase, Biochimica et Biophysica Acta 1993,1142, 83-87

Yan Xiao, Liu Cuihua and Zhang Jinglin, The Synthesis of 3-aminosalicyl-N-(9'-decenyl)amide, Journal of Central China Normal University 1993, 27, 348-351

Chun Liu, Jian-xing Xu, Yan Xiao and Lian-quan Gu, Inhibition of succinate-ubiquinone reductase by nitrosalalicyl-N-alkylamides, Biochimica et Biophysica Acta 1991, 1057, 373-376

Lian-quan Gu, Yan Xiao and Han-bin Hu, Synthesis, oxidation-reduction potentials and biological activity of 1,4-benzoquinone derivatives, Chinese Journal of Organic Chemistry 1991, 11, 481-487

Jian-xing Xu, Yan Xiao and Lian-quan Gu, New inhibitor 3-nitrosalicyl-N-alkylamides affected on ubiquinone reactions of respiratory chain, Acta Biochemica et Biophsica Sinica 1991, 23, 513-519

Lian-quan Gu and Yan Xiao, Synthesis of 2,6-dimethoxy-3-methyl-5-alkyl-1,4-benzoquinones, Journal of Central China Normal University 1990, 24, 169-172

Jian-xing Xu, Yong-li Zhong, Yan Xiao and Lian-quan Gu, The inhibitory effect 3-nitro-N-methyl salicylamide on succinate-cytochrome c reductase, Chinese Biochemical Journal 1987, 3, 139-145

Shu-lian Li, Jian-xing Xu, Yan Xiao and Lian-quan Gu, Photoaffinity labeling studies of ubiquinone binding site in succinate-cytochrome c reductase with tritiated quinone derivatives. Acta Biochemica et Biophysica Sinica 1987, 19, 527-531

Lian-quan Gu, Zhi-gang Jiun, Yan Xiao and Yong-li Zhong, Synthesis of omega-bromo-alkyl-allylic-alcohol Compounds, Journal of Central China Normal University 1986, 20, 303-30